Spectrum and Immunovirological Determinants of Tumours Among People Living with HIV in Uganda: A Retrospective Cohort Study from a Specialised HIV Centre, 2017 to 2026

This retrospective cohort study of 217 people living with HIV in Uganda (2017–2026) reveals that despite high viral suppression rates, malignancies remain predominant and are strongly driven by Kaposi sarcoma and immunovirological factors such as low pre-ART CD4 counts and advanced clinical stage, highlighting the need for improved early screening and immune reconstitution strategies.

The Gist

Imagine the human immune system as a security team guarding a castle (the body). When HIV enters, it doesn't just break the gates; it fires the security guards, leaving the castle vulnerable to invaders. For a long time, doctors had a powerful new tool: Antiretroviral Therapy (ART). Think of ART as a high-tech shield that stops the HIV virus from attacking, allowing the security team to slowly rebuild.

This paper is like a security audit conducted at a specialized hospital in Kampala, Uganda, looking at what happened between 2017 and 2026. The researchers wanted to know: "Even though we have this high-tech shield, what kind of 'invaders' (tumors) are still getting in, and who is most at risk?"

Here is the story of their findings, broken down simply:

1. The Main Invader: The "Kaposi" Ghost

Even though the HIV virus was stopped in most patients (the shield was working), the most common "invader" found was Kaposi Sarcoma (KS).

• The Analogy: Imagine the castle has a specific, stubborn ghost (a virus called HHV-8) that loves to hide in the walls. Even when the main attacker (HIV) is locked out, this ghost can still wake up and cause trouble if the security team is too weak to catch it.
• The Finding: KS made up nearly half of all the cancer cases found. It was the most frequent type of tumor, especially in men.

2. The "Shield" Paradox

The study found something surprising: Most of the people who got cancer were actually doing well on their medication.

• The Analogy: It's like a castle where the main gate is locked tight (the virus is suppressed), but the walls are still crumbling because the security guards haven't fully recovered their strength.
• The Finding: About 86% of the people who developed cancer had their HIV virus under control. This tells us that just having the virus suppressed isn't enough to stop all cancers. The "security team" (immune system) needs more than just a shield; it needs time to fully rebuild.

3. The "Late Arrival" Problem

The researchers looked at when people started their treatment and found a clear pattern.

• The Analogy: Think of the immune system as a garden. If you start watering it (ART) when the plants are already withered and dying (low CD4 count/advanced disease), it takes a very long time for them to recover, and some might never fully heal. If you start watering them while they are still green, they bounce back quickly.
• The Finding: People who started treatment when they were very sick (low immune counts) were much more likely to get cancer later on. Those who started treatment early, while their immune systems were still strong, rarely got these tumors. The damage done by waiting was "durable"—it stuck around even after years of treatment.

4. The "First Year" Danger Zone

There was a spike in cancer diagnoses right after people started their new medication.

• The Analogy: Imagine turning on a bright light in a dark room. Suddenly, you can see all the dust bunnies and spiders that were hiding in the shadows.
• The Finding: Many cancers were found within the first year of treatment. This happens for two reasons:
  1. The immune system wakes up and starts fighting the hidden "ghosts" (like KS) that were already there, making them visible (this is called IRIS).
  2. Doctors are looking more closely at patients when they first start treatment, so they find tumors that were already hiding.

5. The "Ghost" vs. Other Invaders

The study noticed that the Kaposi Sarcoma "ghost" was different from other cancers.

• The Analogy: Kaposi Sarcoma is like a lightning strike—it hits very fast and hard when the immune system is at its weakest. Other cancers are more like slow-growing weeds that take years to appear, usually in people who have been on treatment for a long time.
• The Finding: Patients with Kaposi Sarcoma had much lower immune counts and had been on treatment for a much shorter time than patients with other types of cancer.

6. The "Benign" Crowd

Not every tumor was a scary cancer.

• The Analogy: Some of the lumps found were like harmless garden gnomes (benign tumors) rather than monsters.
• The Finding: About 37% of the tumors found were benign (non-cancerous). In women, the most common "lump" was a harmless uterine fibroid. In men, it was an enlarged prostate. These take up hospital resources but aren't life-threatening like the "monsters" (cancers).

The Bottom Line

This paper tells us that in Uganda, even with excellent HIV medication, Kaposi Sarcoma remains the biggest cancer threat.

The key lesson is that timing matters. If you wait too long to start treatment and your immune system gets too weak, you might carry a "scar" that makes you vulnerable to cancer later, even if your virus is eventually controlled. The study suggests that doctors need to keep a close eye on patients, especially in the first year of treatment and for those who started treatment late, because the "security team" might still be recovering its strength.

Technical Summary

1. Problem Statement and Research Gap

Despite the global scale-up of antiretroviral therapy (ART), People Living with HIV (PLHIV) in Sub-Saharan Africa continue to bear a disproportionate burden of HIV-associated malignancies. While high-income settings have seen a shift toward non-AIDS-defining cancers (NADCs) due to an aging population, the epidemiological transition in East Africa remains incomplete.

• Key Gaps: There is a lack of systematic characterization of the tumor spectrum in the dolutegravir (DTG) era within routine HIV care settings in Uganda. Existing data often lack granular immunovirological context (e.g., viral load, CD4 nadir, WHO stage at ART initiation) or fail to distinguish between benign and malignant neoplasms.
• Objective: To describe the spectrum, malignant fraction, and immunovirological determinants of tumors diagnosed at Mildmay Hospital, a specialized HIV center in Kampala, Uganda, spanning the transition from efavirenz (EFV) to DTG-based first-line ART.

2. Methodology

• Study Design: Retrospective observational cohort analysis.
• Setting: Mildmay Hospital and Mildmay Research Centre, Kampala, Uganda.
• Population: 220 tumor records from 217 unique PLHIV registered between November 2017 and January 2026.
• Data Sources: Electronic medical records with ICD-10 coded diagnoses, ART history, and virological/immunological data.
• Variables:
  • Demographics: Age, sex.
  • Immunovirological: CD4 count at ART initiation, WHO clinical stage at ART initiation, HIV RNA (viral load) at tumor diagnosis (suppressed <1,000 copies/mL vs. unsuppressed).
  • Treatment: ART duration, ART backbone (DTG-based, EFV-based, or PI/NVP-based).
• Statistical Analysis:
  • Tumors classified as malignant or benign.
  • Bivariate associations tested using $\chi^2$, Fisher's exact tests, and Mann–Whitney U tests.
  • Crude Odds Ratios (OR) calculated for dichotomous comparisons.
  • Note: No multivariable regression was performed; the study is descriptive and hypothesis-generating.

3. Key Results

A. Tumor Spectrum and Malignancy

• Overall Malignancy Rate: 62.7% (138/220) of tumors were malignant; 37.3% were benign.
• Dominant Malignancy: Kaposi Sarcoma (KS) was the most frequent malignancy (65 cases; 47.1% of all malignant cases).
• Other Malignancies: Hematopoietic malignancies (23.2%) and malignant gynecological tumors (7.2%).
• Benign Dominance: Gynecological tumors were the largest disease group overall (25% of total), but 81.8% were benign (uterine leiomyomas).

B. Immunovirological Determinants

• Viral Suppression Paradox: Among patients with viral load data, 85.9% were virally suppressed at the time of tumor diagnosis. Crucially, 52.2% of suppressed patients still presented with malignant tumors. This indicates that viral suppression alone does not eliminate cancer risk.
• Pre-ART Immune Status:
  • CD4 Count: Median CD4 at ART initiation was significantly lower in malignant cases (147 cells/µL) compared to benign cases (476 cells/µL; p<0.001).
  • WHO Stage: Advanced WHO stage (III/IV) at ART initiation was strongly associated with malignancy (OR 3.53; p=0.002). 96% of patients starting ART at Stage IV developed a malignant tumor.
• Timing of Diagnosis: Malignancy risk was highest in the early ART period. 87.1% of patients diagnosed within ≤12 months of ART initiation had malignant tumors, compared to 48.4% in those on ART >120 months.

C. Kaposi Sarcoma (KS) vs. Other Malignancies

A distinct immunovirological profile was identified for KS compared to other cancers:

• CD4 Count: KS patients had a median pre-ART CD4 of 136 cells/µL, significantly lower than non-KS malignancies (269 cells/µL).
• ART Duration: KS was diagnosed much earlier (median 4 months post-ART) compared to other malignancies (86 months).
• Viral Status: Viral suppression rates were similar between KS and non-KS groups (~81%), reinforcing that KS arises in immunologically vulnerable but virally suppressed individuals.

D. Demographic and Regimen Factors

• Sex: Men had a significantly higher malignant fraction (79.3%) than women (50.8%), driven by the high prevalence of KS in men and benign fibroids in women.
• ART Regimen: No significant difference in malignancy rates was found between DTG-based, EFV-based, or other regimens (p=0.992).

4. Key Contributions

1. First DTG-Era Profile: Provides the first immunovirologically contextualized description of tumors in a Ugandan specialized HIV center during the transition to DTG-based therapy.
2. Quantification of the "Suppression Paradox": Demonstrates that the majority of HIV-associated cancers in this setting occur in patients who are virally suppressed, challenging the notion that viral load is a sufficient proxy for cancer risk.
3. Distinct KS Phenotype: Establishes that KS in this cohort arises in a more severe immunological context (lower CD4, shorter ART duration) than other HIV-associated malignancies, suggesting different mechanistic pathways (e.g., HHV-8 reactivation due to incomplete immune reconstitution).
4. Benign vs. Malignant Burden: Highlights that while malignancies dominate the cancer burden, benign neoplasms (specifically uterine leiomyomas) constitute a significant portion of the diagnostic workload in HIV clinics.

5. Significance and Implications

• Clinical Practice:
  • Risk Stratification: Viral load status alone is insufficient for cancer risk stratification. Clinicians must prioritize patients with a history of low pre-ART CD4 counts and advanced WHO stage.
  • Early Surveillance: Systematic tumor screening (dermatological, lymph node, symptom review) should be embedded in the first year of ART initiation to catch unmasking IRIS-associated cancers and occult malignancies.
  • Lifelong Monitoring: Given the high rate of malignancy in suppressed patients, lifelong cancer surveillance is necessary regardless of viral suppression status.
• Public Health Policy:
  • Prevention: The findings reinforce the urgency of early HIV testing and linkage to care to prevent the irreversible immune damage that predisposes patients to cancer.
  • Screening: Integration of cervical cancer screening and HPV vaccination is critical, as invasive cervical cancer remains a preventable signal in this population.
• Research Agenda: The study establishes the foundation for a prospective HIV-oncology cohort to investigate mechanisms of immune senescence, incomplete reconstitution, and oncoviral co-infection (specifically HHV-8) in the DTG era.

Conclusion: Even in the era of effective viral suppression, HIV-associated malignancies in Uganda remain predominantly malignant and dominated by Kaposi Sarcoma. The risk is heavily concentrated in patients who initiated ART late with severe immunosuppression, highlighting the need for targeted, lifelong cancer surveillance strategies that go beyond viral load monitoring.